A highly stereoselective total synthesis of (+)-9-epi-dictyostatin

Article abstract of DOI:10.1002/ejoc.201001018

The total synthesis of (+)-9-epi-dictyostatin (1b), a diastereomer of the antimitotic marine-sponge-derived macrolide (-)-dictyostatin (1a), was achieved by creating 11 stereogenic centers and 4 stereogenic double bonds with a high level of stereocontrol.

Full text of DOI:10.1002/ejoc.201001018

SHORT COMMUNICATION
DOI: 10.1002/ejoc.201001018
A Highly Stereoselective Total Synthesis of (+)-9-epi-Dictyostatin
Chiara Zanato,[a] Luca Pignataro,[a] Andrea Ambrosi,[a] Zhongyan Hao,[a] and
Cesare Gennari*[a]
Dedicated to Prof. José Barluenga on the occasion of his 70th birthday
Keywords: Antitumor agents / Asymmetric synthesis / Macrocycles / Natural products / Total synthesis
The total synthesis of (+)-9-epi-dictyostatin (1b), a dia-
stereomer of the antimitotic marine-sponge-derived macro-
lide (–)-dictyostatin (1a), was achieved by creating 11 stereo-
genic centers and 4 stereogenic double bonds with a high
level of stereocontrol. The yield for the 29-step longest linear
sequence from Roche ester was 1.53%. The final key steps
to this unnatural product were the vinylzincate C10–C26 ad-
dition to aldehyde C1–C9 (leading surprisingly to a complete
stereoselectivity for the 9R-epimer), followed by Yamaguchi
macrolactonization and global deprotection.
Introduction
The sponge-derived macrolide (–)-dictyostatin (1a,
Scheme 1) has been reported to be a potent, paclitaxel-like
inducer of tubulin polymerization and to inhibit human
cancer cell proliferation at low nanomolar concentrations,
with activity somewhat superior to the already very active
discodermolide.[1] With the recent withdrawal of discod-
ermolide from clinical development[2] the importance of
dictyostatin further increases. Moreover, (–)-dictyostatin is
also extremely potent against paclitaxel-resistant human
cancer cell lines overexpressing the P-glycoprotein efflux
pump.[1] The structure of (–)-dictyostatin (1a) with full
stereochemical assignments was established by Paterson
and co-workers a few years ago (2004),[3] and four total
syntheses were completed in the period 2004–2007.[4]
A
growing number of research groups have recently been in-
volved in targeting this interesting natural product, and the
syntheses of several analogs (e.g., desmethyldictyostatins,
epi-dictyostatins, bis-epi-dictyostatins, hydrodictyostatins,
methoxydictyostatins),[5] discodermolide/dictyostatin hy-
brids,[6] and various fragments and synthetic intermedi-
ates[7] have been described. The development of dictyostatin
analogs is an appealing goal from a pharmaceutical per-
spective, which provides interesting opportunities for struc-
tural simplification whilst maintaining biological potency,
and for better understanding the structure–activity relation-
ships of this class of antitumor agents. In this communica-
[a] Università degli Studi di Milano, Dipartimento di Chimica
Organica e Industriale, Centro Interdipartimentale C.I.S.I.,
Via G. Venezian 21, 20133 Milan, Italy
Fax: +39-02-50314072
E-mail: cesare.gennari@unimi.it
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201001018.
Scheme 1. Retrosynthetic approach to (+)-9-epi-dictyostatin (1b),
with key reactions involved and associated diastereomeric ratios.
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C. Zanato, L. Pignataro, A. Ambrosi, Z. Hao, C. Gennari
SHORT COMMUNICATION
tion, we describe a highly stereoselective total synthesis of Marshall–Tamaru palladium-catalyzed allenylzinc ad-
(+)-9-epi-dictyostatin (1b), building on our prior work in dition[13] with the mesylate of (R)-3-butyn-2-ol gave alcohol
this field.[7j,7k] Our retrosynthetic approach, shown in 12 (82% over two steps) with a high level of diastereoselec-
Scheme 1, disconnects the macrolide ring into two key in- tivity (Ͼ98:2) in favor of the desired anti,syn adduct. TBS
termediates: C1–C9 aldehyde 2, prepared from the corre- protection of alcohol 12 afforded alkyne 13, which was then
sponding alcohol,[7k] and C10–C26 vinyl iodide 3, prepared lithiated with nBuLi and converted into the corresponding
by taking advantage of a synthetic route similar to that re- alkynyl iodide 14 in quantitative yield (Scheme 3). Re-
ported for fragment C10–C23.[7j]
duction of compound 14 with diimide[5d,14] provided (Z)-
vinyl iodide 15 as a single diastereoisomer (Z/E Ͼ 100:1) in
excellent yield (92%). The primary tert-butyldimethylsilyl
ether of 15 was selectively cleaved (HF-Py, THF/Py, 80%)
to give compound 16, which was converted into aldehyde
Results and Discussion
The synthesis of C10–C26 fragment 3 started with the 17 by oxidation with Dess–Martin periodinane. The latter
preparation of propargylic alcohol 7 (Scheme 2), for which compound was treated with (1-bromoallyl)trimethylsilane
we had previously reported[7j] the direct addition of ter- under
Nozaki–Hiyama–Kishi
coupling
conditions
minal alkyne 4 to the aldehyde obtained by reduction of (CrCl2),[15] followed by a Peterson elimination (KOH,
Weinreb amide 5 using the Carreira asymmetric alk- MeOH) to give C10–C26 fragment 3 in good yield (76%, 2
ynylation protocol.[8] However, this procedure proved ca- steps) and excellent diastereoselectivity (Z/E Ͼ 100:1).[16]
pricious and poorly reproducible during scale-up. We thus
Following Ramachandran’s lead,[4d] lithiation of (Z)-
opted for the coupling reaction between alkyne 4[7j] and vinyl iodide 3 (tBuLi) and subsequent treatment with di-
Weinreb amide 5 (prepared according to Smith III and co- methylzinc provided the corresponding lithium (Z)-vinyl-
workers)[9] to form ynone 6 (70%), which was then sub- zincate,[17] which was added to β-silyloxy aldehyde 2 to give
jected to Noyori asymmetric transfer hydrogenation[10] to the coupling product 18 in moderate yield (40%) and excel-
give the desired alcohol 7 in excellent yield (98%) and with lent diastereomeric ratio (Ͼ95:5; Scheme 4).[18] On the basis
a Ͼ100:1 diastereomeric ratio (dr).
of the structural assignment of final product 1b (vide infra),
Acetal 7 was cleaved with DIBAL-H to generate diol 8 the stereochemistry of the newly created stereogenic center
in 75% yield. Hydrogenation (under 4 bar H2 pressure) of in compound 18 turned out to be (9R). We found this out-
propargylic alcohol 8, in the presence of a catalytic amount come quite surprising, as the addition of the same (Z)-vinyl-
(10%) of Wilkinson’s catalyst, afforded the desired satu- zincate to a very similar aldehyde (with the ethyl ester in 2
rated compound 9 (70%), which was then silylated to give instead of the methyl ester) was reported to give an excellent
the fully protected tetraol 10 in 97% yield. Selective re- ratio in favor of the (9S) stereoisomer.[4d]
moval of the benzyl group over the PMB group (H2, Raney-
In principle, compound 18 should be easily conveyed into
Ni, EtOH)[11] furnished primary alcohol 11 in 81% yield. the total synthesis of (–)-dictyostatin (1a) by oxidation of
TPAP/NMO oxidation[12] of alcohol 11 followed by a the (9R)-allylic alcohol to the corresponding 9-ketone, com-
Scheme 2. Synthesis of C10–C23 fragment 13.
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A Highly Stereoselective Total Synthesis of (+)-9-epi-Dictyostatin
Scheme 3. Synthesis of C10–C26 fragment 3.
Scheme 4. Completion of the synthesis of (+)-9-epi-dictyostatin (1b).
pletion of the synthetic sequence (as outlined in Scheme 4) trol reinforces the 1,3-anti stereochemical outcome (model
and reduction of the enone to the (9S)-allylic alcohol C, axial attack).[20] Recently, Curran and co-workers
(NaBH4, CeCl3·7H2O, EtOH, –30 °C)[4a] immediately be- studied the addition of a (Z)-vinyllithium compound to al-
fore final deprotection.
dehyde 2 and reported a ca. 2:1 1,3-anti/1,3-syn dia-
The preference for the 1,3-syn diastereomer observed in stereomeric ratio.[5i] Addition of other (Z)-vinyllithium
compound 18 can be rationalized on the basis of 1,3-asym- compounds to similar aldehydes gave 1,3-anti/1,3-syn ratios
metric induction models thoroughly investigated by ranging from 1.5:1 to 1:1.6.[5d,5i] Apparently, models B and/
Evans.[19] Steric interactions in the aldehyde conformations or C (equatorial attack), leading to the 1,3-syn dia-
are minimized when the β-alkyl substituent (Rβ) is oriented stereomer, start making a substantial impact in these ad-
anti to the Cα–C=O bond as in structures A and B shown dition reactions. Surprisingly, when a lithium dimethylalk-
in Scheme 5. Usually, β-OTBS substituted aldehydes afford enylzincate[17,21] is used, the stereochemical outcome is de-
preferentially the 1,3-anti diastereomer via polar model A, termined only by models B and/or C (equatorial attack),
where dipoles are opposed.[19] When aluminum Lewis acids leading to complete selectivity in favor of the 1,3-syn dia-
(Me2AlCl or MeAlCl2) are used, exceptional chelation con- stereomer.
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C. Zanato, L. Pignataro, A. Ambrosi, Z. Hao, C. Gennari
SHORT COMMUNICATION
(1a).[5c,5i] The new synthetic route is flexible enough to al-
low (i) inversion at C9 by oxidation–reduction[4a,4e] and
(ii) the preparation of other non-natural analogs of dictyos-
tatin [e.g., 12,13-bis-epi-dictyostatin by using the mesylate
of (S)-3-butyn-2-ol in the Marshall–Tamaru palladium-cat-
alyzed allenylzinc addition]. Future work will be focused on
the synthesis of such analogs, which can be insightful for
better understanding the structure–activity relationships of
this class of antitumor agents.
Supporting Information (see footnote on the first page of this arti-
cle): Experimental procedures and characterization data for new
compounds along with copies of the NMR spectra (1H, 13C).
Acknowledgments
We thank the Ministero dellЈUniversità e della Ricerca for financial
support (PRIN prot. 2008J4YNJY) and for a PhD fellowship
(Borsa di dottorato ‘Progetto giovani’ to C.Z.). L.P. thanks Milan
University for a postdoctoral fellowship (“Assegno di ricerca”).
Z.H. (Lanzhou University, PRC) thanks the China Scholarship
Council for a PhD mobility grant.
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Conclusions
A highly stereoselective synthesis of (+)-9-epi-dictyosta-
tin (1b) has been carried out in 1.53% overall yield over 29
steps (longest linear sequence from the Roche ester). Unfor-
tunately, unnatural configuration at C9 is known to cause
a substantial drop in cytotoxicity relative to dictyostatin
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Received: July 19, 2010
Published Online: September 20, 2010
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